The National Ovarian Cancer Prevention and Early Detection Study [CAS 7210] among women at increased genetic risk of ovarian cancer (aka GOG-199) is the cornerstone of CGB's intervention studies research portfolio. It is a non-randomized natural history study of risk-reducing salpingo-oophorectomy (RRSO) versus a novel ovarian cancer screening strategy (the ROCA algorithm). This study closed to new patient enrollment in November 2006, having accrued 2605 high-risk women (1029 surgery arm; 1576 screening arm). Prospective follow-up ended in November 2011, and the final analytic data base is now complete. Recent accomplishments to date include: (1) contributing 1,576 screening subjects to a published pooled analysis (with the Cancer Genetics Network: total = 4,000 subjects) of determinants of baseline CA-125 levels and of the performance characteristics of the ROCA algorithm, which demonstrated that pre-menopausal women should have an upper limit of normal cut-off=52, rather than 35 as customarily used; (2) continued our collaboration with seeking genetic modifiers of BRCA1/2-associated breast and ovarian cancer risk, an effort which has produced 40 published manuscripts, with an additional 7 are currently under review; (3) quantification of the prevalence of clinically-occult ovarian cancers among asymptomatic women undergoing RRSO: 25 (2.6%) of 966 GOG-09199 RRSOs (BRCA1 carriers=4.6%, BRCA2 carriers=3.5%, and non-carriers=0.5% (p=0.0006); (4) documenting that high-risk women WILL comply with an ovarian cancer screening program that entails providing a blood sample every 3 months, a regimen (ROCA: the risk of ovarian cancer algorithm) which produces a significant stage downshift among incident ovarian cancer cases, permits optimal surgical debulking in nearly all new cases, and identifies about 50% of new cancers before they exceed the standard CA125 cutoff of 35 IU/ml. These findings suggest that the ROCA algorithm may represent an important new advance in the world of ovarian cancer screening; (5) demonstrating the poor reproducibility of the diagnosis of fallopian tube mucosal atypia on blinded pathology review, illustrating the need for improved diagnostic criteria; (6) using the prospective follow-up of GOG-0199 study participants to determine that the breast cancer protective effect previously described in relation to RRSO may not be as large as previously estimated. The remaining primary study endpoints related to GOG-0199 are now under analysis, including baseline medical decision-making and quality of life, prospective evaluation of quality of life (stratified by study arm) during 5 years' prospective follow-up, and an analysis of medical decision-making among the 381 women who crossed over from the screening to the surgical arm of this study. The Breast Imaging Pilot Study in Women from BRCA Mutation-Positive Families achieved its accrual goal and prospective follow-up has now ended. Recent findings from this project include: (1) identification of a computer-extracted feature of digital mammograms, mammographic texture, the presence of which signals a two-fold increase in the likelihood of an affected patient being a BRCA1/2 mutation carrier; (2) development of an anthropomorphic phantom for quantitative evaluation of breast MRI images, in collaboration with investigators from the FDA; (3) demonstrating that circulating levels of estrogen and its metabolites are very strongly, positively correlated with levels measured on fluids obtained directly from the breast (nipple aspirate fluid; breast duct lavage supernatant), a finding which suggests that future etiologic studies could utilize the more readily obtainable serum hormone levels as a reliable surrogate measure of exposure at the tissue level. (4) continued collaboration with CIMBA in search of genetic modifiers of BRCA1/2-associated breast and ovarian cancer; (5) a psychosocial analysis of data from Breast Imaging Study patients that revealed that false positive cancer screening test results were not associated with large increases in cancer risk perception, cancer worry or increased uptake of risk-reducing surgery. However, cancer-specific worry was an independent predictor of uptake of risk-reducing surgery; this domain warrants consideration when counseling high-risk women regarding risk-reducing interventions; (6) and a landmark series of 6 publications targeting the special needs of very young (less than age 25) mutation carriers, a population which faces particularly challenging developmental challenges as they navigate the life-shaping decisions of finding a partner, entering the world of work, contemplating family formation, all in the context of concerns regarding the management of their BRCA-associated cancer risk management, including intensive screening and the need for risk-reducing surgery.Li-Fraumeni syndrome (LFS) is a highly penetrant cancer predisposition syndrome most commonly caused by germline mutations in TP53 and associated with brain, adrenal gland, and breast cancers, leukemia, and many other malignancies in children and adults. The cancer-screening component is an integral part of the larger LFS study that opened at the NIH Clinical Center, in June 2012. By mid-2014, more than 200 TP53 individuals were eligible and enrolled. Due to this overwhelming and rapid response to opening the protocol, we met our initial accrual goal for the clinical cohort and closed the clinical cohort to accrual in December 2014. To date, we have screened total of 85 participants with a range of follow-up from 1-4 years (27 males, 58 females with an age range of 5-62 years). Seven cancers have been diagnosed, five screen-detected (one lung, two brain, two breast), plus two interval cancers (one gastric and one new primary breast cancer in a woman who previously had bilateral mastectomy). Of the 85 completed whole body MRIs, 19 had results requiring additional evaluation, including three biopsies, one of which led to a lung cancer diagnosis. One participant had brain MRI findings consistent with multiple sclerosis. The breast cancer diagnoses were made by breast MRI screening and targeted brain MRI identified the two brain tumors (a low-grade glioma and a grade 2 astrocytoma). We will analyze the effectiveness of the screening protocol based on its ability to detect early stage cancers, the development of interval cancers, the frequency of false positive screening findings, and participant adherence to this rigorous schedule. Our data will also be included in larger pooled analyses of data from multiple institutions. Our psychosocial studies included the first CEGRM study of LFS families in which ee found that while the number of friendships varied widely, they were usually deep and enduring and were important sources of informational, tangible and emotional support. Longitudinal follow-up of LFS CEGRM participants is planned to explore whether new cancer diagnoses or the death of affected family members changes the social support networks of participants. We plan to describe the cognitive appraisal of cancer risk and emotional well being in individuals and families with known or suspected LFS or LFL at enrollment in the study and are evaluating data from 285 participants assessed using standardized questionnaires for stress, distress, depression, anxiety, somatization, coping, cancer risk appraisal, and cancer worry. Additionally, we have also incorporated qualitative interviews of LFS families designed to improve understanding of their day-to-day challenges